Chemotactic migration of the Lyme disease spirochete (Borrelia burgdorferi) to salivary gland extracts of vector ticks.

Shih, Chien-Ming; Chao, Li-Lian; Yu, Chia-Peng

doi:10.4269/ajtmh.2002.66.616

Cited by 41 publications

(43 citation statements)

References 36 publications

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“…Spirochetes also must cross physical barriers (i.e., peritrophic and basement membranes) and evade the tick's innate immune defenses, which includes antimicrobial peptides and defensins, lysozyme, agglutinins/lectins, complement-related molecules, and reactive oxygen species (ROS) (4,(7)(8)(9)(10)(11). In order to migrate into and out of the vector, Borrelia must sense and respond to chemotactic signals encountered within the bite site and midgut, respectively (113,114). Two regulatory systems, the Hk1/Rrp1 TCS and the Rrp2/RpoN/RpoS pathway, are essential for orchestrating the expression of the gene products that B. burgdorferi requires to meet the demands of its enzootic cycle (1,17).…”

Section: Discussionmentioning

confidence: 99%

Cyclic di-GMP Modulates Gene Expression in Lyme Disease Spirochetes at the Tick-Mammal Interface To Promote Spirochete Survival during the Blood Meal and Tick-to-Mammal Transmission

et al. 2015

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e Borrelia burgdorferi, the Lyme disease spirochete, couples environmental sensing and gene regulation primarily via the Hk1/ Rrp1 two-component system (TCS) and Rrp2/RpoN/RpoS pathways. Beginning with acquisition, we reevaluated the contribution of these pathways to spirochete survival and gene regulation throughout the enzootic cycle. Live imaging of B. burgdorferi caught in the act of being acquired revealed that the absence of RpoS and the consequent derepression of tick-phase genes impart a Stay signal required for midgut colonization. In addition to the behavioral changes brought on by the RpoS-off state, acquisition requires activation of cyclic di-GMP (c-di-GMP) synthesis by the Hk1/Rrp1 TCS; B. burgdorferi lacking either component is destroyed during the blood meal. Prior studies attributed this dramatic phenotype to a metabolic lesion stemming from reduced glycerol uptake and utilization. In a head-to-head comparison, however, the B. burgdorferi ⌬glp mutant had a markedly greater capacity to survive tick feeding than B. burgdorferi ⌬hk1 or ⌬rrp1 mutants, establishing unequivocally that glycerol metabolism is only one component of the protection afforded by c-di-GMP. Data presented herein suggest that the protective response mediated by c-di-GMP is multifactorial, involving chemotactic responses, utilization of alternate substrates for energy generation and intermediary metabolism, and remodeling of the cell envelope as a means of defending spirochetes against threats engendered during the blood meal. Expression profiling of c-di-GMP-regulated genes through the enzootic cycle supports our contention that the Hk1/Rrp1 TCS functions primarily, if not exclusively, in ticks. These data also raise the possibility that c-di-GMP enhances the expression of a subset of RpoS-dependent genes during nymphal transmission. Borrelia burgdorferi, the causative agent of Lyme disease, is maintained in nature within an enzootic cycle that involves an arthropod vector and vertebrate reservoir hosts, typically, small rodents and birds (1). In the northeastern United States, the primary vector for B. burgdorferi is the black-legged deer tick, Ixodes scapularis (2, 3). Because B. burgdorferi cannot be passaged transovarially, naive larvae acquire spirochetes by feeding on infected reservoir hosts. Successful colonization of the vector requires B. burgdorferi to establish an intimate association with rapidly differentiating, highly endocytic midgut epithelial cells (4-6). In order to accomplish this feat, spirochetes must resist deleterious substances within the midgut lumen, such as host-and tick-derived innate immune effector molecules, reactive oxygen species (ROS), and salivary enzymes imbibed from the feeding site (4, 7-11). At the same time, B. burgdorferi also must alter its metabolic machinery to exploit the availability of alternative carbon sources (e.g., glycerol, N-acetylglucosamine [GlcNAc], chitobiose) as the supply of ingested glucose diminishes (12-15). During nymphal transmission, spirochetes are almost certai...

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Section: Discussionmentioning

confidence: 99%

Cyclic di-GMP Modulates Gene Expression in Lyme Disease Spirochetes at the Tick-Mammal Interface To Promote Spirochete Survival during the Blood Meal and Tick-to-Mammal Transmission

et al. 2015

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“…B. burgdorferi is unique in its ability to swim and penetrate into highly viscous environments, such as the host connective tissue, during infection (11,14,24,56). The spirochete is also chemotactic to several host components (3,52,53), such as the extract of tick salivary glands and host serum. The nature of its complicated life cycle strongly suggests the requirement for a sensory guided movement in response to changes in stimuli during transmission.…”

Section: Discussionmentioning

confidence: 99%

“…Bacterial chemotaxis may guide the migration of spirochetes from the tick gut toward the salivary glands. An extract of tick salivary glands is a strong attractant to B. burgdorferi (53). Thus, the failure to recognize and swim toward attractants may block the early migration and transmission process.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, our recent report describes a fliG1 mutant strain which is unable to translate in highly viscous media and fails to cause infection in a mouse model of the disease (29). Since bacterial motility is directed by chemotaxis (61), many Lyme disease researchers have long believed that chemotaxis may also be involved in the disease processes (11,28,44,47,52,53) (e.g., facilitating spirochete migration from the tick gut to the salivary glands and initiating a new infection and/or dissemination from the site of deposition into the circulatory system of mammalian hosts). However, supporting evidence is very limited, owing primarily to the difficulty of constructing and complementing mutants in virulent strains of B. burgdorferi.…”

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confidence: 99%

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Borrelia burgdorferi Needs Chemotaxis To Establish Infection in Mammals and To Accomplish Its Enzootic Cycle

et al. 2012

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ABSTRACTBorrelia burgdorferi, the causative agent of Lyme disease, can be recovered from different organs of infected animals and patients, indicating that the spirochete is very invasive. Motility and chemotaxis contribute to the invasiveness ofB. burgdorferiand play important roles in the process of the disease. Recent reports have shown that motility is required for establishing infection in mammals. However, the role of chemotaxis in virulence remains elusive. Our previous studies showed thatcheA2, a gene encoding a histidine kinase, is essential for the chemotaxis ofB. burgdorferi. In this report, thecheA2gene was inactivated in a low-passage-number virulent strain ofB. burgdorferi. In vitroanalyses (microscopic observations, computer-based bacterial tracking analysis, swarm plate assays, and capillary tube assays) showed that thecheA2mutant failed to reverse and constantly ran in one direction; the mutant was nonchemotactic to attractants. Mouse needle infection studies showed that thecheA2mutant failed to infect either immunocompetent or immunodeficient mice and was quickly eliminated from the initial inoculation sites. Tick-mouse infection studies revealed that although the mutant was able to survive in ticks, it failed to establish a new infection in mice via tick bites. The altered phenotypes were completely restored when the mutant was complemented. Collectively, these data demonstrate thatB. burgdorferineeds chemotaxis to establish mammalian infection and to accomplish its natural enzootic cycle.

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“…In the mammalian host, motility may be important for the spirochetes to penetrate the bloodstream after being deposited in the skin by the tick bite and also for specific tissue and organ localization (32,55). For the cycle to be completed, salivary proteins and other compounds could conceivably serve as attractants during tick feeding (12,32,53). This chemotactic signaling would result in the spirochetes concentrating at the site of the tick bite for cycle continuation.…”

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confidence: 99%

Identification of Specific Chemoattractants and Genetic Complementation of a Borrelia burgdorferi Chemotaxis Mutant: Flow Cytometry-Based Capillary Tube Chemotaxis Assay

Bakker¹,

Li²,

Miller

et al. 2007

Appl Environ Microbiol

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Measuring the chemotactic response of Borrelia burgdorferi, the bacterial species that causes Lyme disease, is relatively more difficult than measuring that of other bacteria. Because these spirochetes have long generation times, enumerating cells that swim up a capillary tube containing an attractant by using colony counts is impractical. Furthermore, direct counts with a Petroff-Hausser chamber is problematic, as this method has a low throughput and necessitates a high cell density; the latter can lead to misinterpretation of results when assaying for specific attractants. Only rabbit serum and tick saliva have been reported to be chemoattractants for B. burgdorferi. These complex biological mixtures are limited in their utility for studying chemotaxis on a molecular level. Here we present a modified capillary tube chemotaxis assay for B. burgdorferi that enumerates cells by flow cytometry. Initial studies identified N-acetylglucosamine as a chemoattractant. The assay was then optimized with respect to cell concentration, incubation time, motility buffer composition, and growth phase. Besides N-acetylglucosamine, glucosamine, glucosamine dimers (chitosan), glutamate, and glucose also elicited significant chemoattractant responses, although the response obtained with glucose was weak and variable. Serine and glycine were nonchemotactic. To further validate and to exploit the use of this assay, a previously described nonchemotactic cheA2 mutant was shown to be nonchemotactic by this assay; it also regained the wild-type phenotype when complemented in trans. This is the first report that identifies specific chemical attractants for B. burgdorferi and the use of flow cytometry for spirochete enumeration. The method should also be useful for assaying chemotaxis for other slow-growing prokaryotic species and in specific environments in nature.Lyme disease is caused by the motile spirochete Borrelia burgdorferi. This disease is the most prevalent arthropod-borne infection in the United States, with 19,804 cases reported in 2004 (11). The clinical course of B. burgdorferi infections includes symmetrical spread of the spirochetes through the dermis resulting in a rash referred to as erythema migrans and invasion of the blood and deep organs (6). Disease manifestations also include arthritis, cardiac abnormalities, and neuropathies. The life cycle of B. burgdorferi involves transmission from a tick vector to mammals or birds and back to the tick over the course of several seasons (54).A robust motility-and-chemotaxis system is likely to be vital for B. burgdorferi in its overall life cycle. Many of the motility and chemotaxis genes are expressed in both the tick and the mammalian host, and several are upregulated in the laboratory that mimic in vivo conditions (8,16,21,45,48,57). Furthermore, approximately 6% of its chromosomal genome encodes putative chemotaxis and motility genes (18) and between 10 and 14% of the total cellular protein is composed of flagellar filament proteins (42). Thus, this system is both evidentl...

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Chemotactic migration of the Lyme disease spirochete (Borrelia burgdorferi) to salivary gland extracts of vector ticks.

Cited by 41 publications

References 36 publications

Cyclic di-GMP Modulates Gene Expression in Lyme Disease Spirochetes at the Tick-Mammal Interface To Promote Spirochete Survival during the Blood Meal and Tick-to-Mammal Transmission

Cyclic di-GMP Modulates Gene Expression in Lyme Disease Spirochetes at the Tick-Mammal Interface To Promote Spirochete Survival during the Blood Meal and Tick-to-Mammal Transmission

Borrelia burgdorferi Needs Chemotaxis To Establish Infection in Mammals and To Accomplish Its Enzootic Cycle

Identification of Specific Chemoattractants and Genetic Complementation of a Borrelia burgdorferi Chemotaxis Mutant: Flow Cytometry-Based Capillary Tube Chemotaxis Assay

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